MDMA (Ecstasy) Flashcards
(11 cards)
MDMA history
MDMA is 3,4-methylenedioxymethamphetamine.
Alternatively known as Ecstasy, Molly or Mandy for the crystal form, or as E, X or XTC for tablet forms.
MDMA was synthesised in 1912 by Anton Köllisch, Merck, Germany and patented in 1914 as a precursor for other potential therapeutics. It was a potential anorectic agent.
Toxicology was explored in the 50s.
In the 80s, potential psychotherapeutic use was explored. Oral administration of 75-175 mg evoked tachycardia, elevated BP and transient anxiety, but these are effects observed in a clinical setting.
In 1985, the Drug Enforcement Administration (DEA) declared MDMA a schedule 1 drug.
MDMA started to gain popularity in the 90s, just as interest in LSD was going down.
In 2011, MDMA was used in a clinical trial for PTSD.
Similar drugs
Drugs with a similar structure to MDMA include amphetamine, methylphenidate, mescaline and fenfluramine.
Fenfluramine was prescribed as a weight loss medication until ~15 years ago as it was thought to increase metabolism. It is similar to methamphetamine and stimulates the breakdown of lipids.
Mescaline has been used for mystical and hallucinogenic experiences.
Emergence of ecstasy
The emergence of MDMA in the US coincided with the emergence of rave culture.
In the mid 80s Acid House music originated in the US. Unlicensed clubs played rhythmic electronic music with synchronised video/light shows all night or even all weekend.
There was widespread availability of MDMA as 75-150 mg tablets in bright colours with bold patterns and logos - some styles were associated with particular producers.
These had a latency of 20-60 mins, peaking 60-90 mins, lasting for 3-5 h.
It was easier to supply pills at these unlicensed clubs than a wide range of alcohol as these require less space, which contributed to their availability and popularity.
Effects of ecstasy
The subjective impact of MDMA is more profound in females.
It causes:
- Interoception, the ability to sense and interpret signals from inside your body - perception of self, very different from other dissociative drugs available at the time
- Relaxed, euphoric state
- Emotional openness and empathy (empathogen)
- Enhanced tactile sensation (entactogen) ⇒ people in rave culture were hugging more than fighting, giving the drug a positive reputation.
- Reduced inhibition and negative thoughts
- Increased intensity of sounds/colours, weakly hallucinogenic in <20% of users, reinforced by light flashes in the environment
In animal models, when compared to cocaine and heroin, MDMA is considered a moderate reinforcer, so it has a lower association with the development of dependence.
The subjective impact of MDMA is context dependent.
- Clubs/parties: increased motor activity, reduced sense of identity, dissociation from the environment
- Individually/quiet context: increased clarity and capacity for concentration, interoceptivity (emotional awareness, communicability, etc.)
- Lab environment: childish/child-like and reflection on childhood, mood fluctuations. These are more negative responses.
This gradation of responses is classical for mood-altering drugs, but particularly marked for MDMA.
The effects also show dose dependence. Higher doses show increased hedonic and arousal behaviours. Sociability is consistently increased, but effects on empathy are less consistent.
MDMA mechanism of action
MDMA acts at multiple cell surface monoamine transporters with different potencies: SERT/SLC6A4 > NET/SLC6A2 > DAT/SLC6A3
It also acts at vesicular monoamine transporters including VMAT1/SLC18A1 and VMAT2/SLC18A2.
MDMA reverses the flow of these transporters, leading to increased extracellular monoamine concentrations and enhanced neurotransmission.
MDMA also shows low affinity binding to adrenoceptors, most 5-HT receptors and dopamine receptors.
- 5HT2B (Gq coupled) and TA1 (Gs/Gq) receptors binding at <1 µM
- 5HT2B receptors are associated with psychedelic effects - binding by MDMA is weak, which explains why only weak effects are produced in 20% of users
- TA1 receptors are trace amine receptors with major species variation. Activation increases dopamine signalling.
Trace amine signalling
TA1 receptors are activated by trace amines: tyramine > β-phenylethylamine > octopamine = dopamine
Trace amines are found at very low levels in the mammalian brain.
Urinary tyramine levels drop in schizophrenia and bipolar disorder, but it is not known if this is a causal link, and MAO inhibitors, used to treat depression, increase trace amine levels more than other amine transmitters.
Trace amine receptors show an overlap and influence on dopamine levels and signalling. They may form pre- and post-synaptic heterodimers with dopamine receptors → converging signalling pathways and modulation.
MDMA acts as a partial agonist at rat TA1 receptors, as do amphetamine, methamphetamine (meth, crystal meth) and LSD.
TA1 activation can influence the dopamine transporter (DAT), leading to a reduction in dopamine reuptake, thereby increasing the availability of dopamine in the synapse.
MDMA user numbers
Europe is an important global supply source, with most MDMA production concentrated in or around the Netherlands.
Indications suggest increasing levels of MDMA production within Europe, following a recent period in which production volumes are thought to have declined.
The number of MDMA laboratories dismantled in the EU rose to 48 in 2022 (25 in 2021), while seizures of the controlled precursor PMK and its glycidic derivatives increased markedly in 2022, to 19.9 tonnes (2.6 tonnes in 2021).
This may reflect an increase in the production of the drug for global markets and a general rebound following a decline related to the COVID-19 pandemic.
However, in 2022, the quantity of MDMA tablets seized in the EU declined by nearly a third, while the quantity of MDMA powder seized declined slightly.
The MDMA content of tablets and the purity of powders continued to decline in 2022 from a pre-pandemic peak in 2019.
The Netherlands, Czechia and Ireland are hotspots for MDMA use in the EU.
The purity of Ecstasy pills is generally high. Other substances are occasionally added to give the pill a kick, such as synthetic cathinones (khat plant compound derivatives, amphetamines) and caffeine. These are stimulants.
The lifetime experience of ecstasy and other class A drugs has been increasing over the last 30 years.
Frequent users of ecstasy have always been low compared to cannabis or even cocaine users, but numbers also decreased since 2003.
Adverse events and controversies
MDMA consumption shows a number of amphetamine-like acute adverse events including: tachycardia, palpitations, dry mouth, bruxism (grinding teeth), trismus (tightening of jaw muscles), diaphoresis/hyperhidrosis (excessive sweating) and insomnia.
In high doses, MDMA consumption can result in rhabdomyolysis and cardiac arrhythmias.
On rare occasions, this can lead to severe hyperthermia, resulting in liver, kidney, and cardiovascular system failure and death. This is amplified by high ambient temperatures and intense exercise, which are both present at raves.
In the 2000s, there was a publication in ‘In Science’ describing the use of MDMA causing dopaminergic toxicity, and this was observed at common recreational doses.
However, this article was retracted after the authors found that the drug was mislabelled and they were in fact using methamphetamine, and not MDMA. This however still soiled the reputation of the drug.
There is no evidence that MDMA causes neurotoxicity, but there are other adverse effects we are confident about.
Following acute use, MDMA users show short-term memory deficits manifesting as worse performance on learning and memory tasks.
Tolerance is observed with repeated administration. Anecdotally, pleasurable effects decline while side effects increase.
Cardiovascular risks are similar to those of cocaine. This is due to elevated monoamine levels.
Withdrawal syndrome includes fatigue, loss of appetite, depression and trouble concentrating. These are not major.
Ecstasy and amphetamine are not responsible for many deaths due to overdose. In fact, they cause less than paracetamol and antidepressants. Paracetamol and antidepressants are however a lot more widely used.
David Nutt wrote a controversial paper comparing the number of deaths caused by ‘equasy’ (horse riding) to those caused by ecstasy, arguing that the former is more
dangerous.
*MDMA for PTSD
MDMA-assisted therapy was investigated in a phase 3 trial for individuals with severe PTSD. Participants were administered MDMA or a placebo, along with manualized therapy.
The primary outcome measure was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and the secondary outcome measure was the Sheehan Disability Scale (SDS).
MDMA-assisted therapy resulted in a significant reduction in CAPS-5 scores compared to placebo. There was also a significant decrease in SDS total score.
MDMA did not induce adverse events of abuse potential, suicidality, or QT prolongation. The treatment was safe and well-tolerated, even in those with comorbidities.
67% of participants in the MDMA group no longer met PTSD diagnostic criteria, compared to 32% in the placebo group. 33% of participants in the MDMA group met remission criteria versus 5% in the placebo group.
The study suggests that MDMA-assisted therapy may help patients revisit and process traumatic content without becoming overwhelmed. It may also facilitate recall of memories with greater self-compassion and less PTSD-related shame and anger.
MDMA in autism-related social anxiety
MDMA-assisted psychotherapy was investigated as a treatment for social anxiety in autistic adults.
Ina double-bling pilot study, participants received MDMA (75 to 125 mg) or a placebo during two 8-hour psychotherapy sessions.
Improvement in Liebowitz Social Anxiety Scale (LSAS) scores from baseline to the primary endpoint was significantly greater in the MDMA group compared to the placebo group.
Social anxiety remained the same or continued to improve for most participants in the MDMA group after completing the active treatment phase. The study demonstrated rapid and durable improvement in social anxiety symptoms in autistic adults.
The rationale behind this effect is that MDMA is primarily a potent releaser of serotonin and noradrenaline, and to a lesser extent dopamine. MDMA also promotes release of the neurohormone oxytocin (OT), which is associated with social affiliation and attenuates amygdalar response to anxiogenic stimuli.
MDMA vs Methamphetamine
3,4-methylenedioxy-methamphetamine (MDMA, “Ecstasy”) and methamphetamine (METH, “Crystal Meth”) share structural similarities but have distinct psychotropic profiles due to specific neurochemical actions.
Recrystallized methamphetamine hydrochloride forms colorless crystals, known as “crystal meth”, “glass”, and “ice”.
The (S)-(+)-enantiomer of methamphetamine is the illicit drug and active neurostimulant, while the (R)-(−)-enantiomer is found in over-the-counter decongestants.
Methamphetamine increases dopamine, serotonin, and noradrenaline concentrations in the brain by increasing their release and interfering with transporter action, stimulating motivation, movement, pleasure, and reward centers.
The rapid release of dopamine causes the “rush” experienced by users who inhale vaporized methamphetamine.
Oral methamphetamine is FDA-approved as a prescription medication for attention-deficit disorder in children and short-term obesity treatment as an appetite suppressant.
According to the United States National Survey on Drug Use and Health, 4.7% of responders (over 12 million people) indicated they had used methamphetamine at least once in their life.
Adverse effects include neuropsychiatric symptoms like anxiety, paranoia, and hallucinations. Chronic use can lead to myocardial infarction, stroke, and “meth mouth”, which is severe tooth decay.
Methamphetamine use during pregnancy can cause growth restriction and lower birth weight in infants.
Withdrawal symptoms are relatively mild, including dysphoria, irritability, and fatigue.
